medwireNews: Dabrafenib plus trametinib is superior to standard chemotherapy in untreated pediatric patients with low-grade glioma carrying BRAF V600 mutations, indicates a randomized trial.
The combination of “dabrafenib plus trametinib resulted in significantly more responses, longer progression-free survival [PFS], and a better safety profile than standard chemotherapy as first-line therapy,” report the investigators in The New England Journal of Medicine.
They continue: “Overall, these findings show the value of early molecular testing in children with low-grade glioma to determine the presence or absence of BRAF V600 mutations.”
The phase 2 study included 110 patients aged 1–17 years who had low-grade glioma with BRAF V600 mutations and were due to receive first-line systemic therapy. Participants were randomly assigned to receive the BRAF inhibitor dabrafenib at a dose of 4.50 or 5.25 mg/kg depending on age plus the MEK1–2 inhibitor trametinib at 0.025 or 0.032 mg/kg, or standard chemotherapy consisting of carboplatin plus vincristine.
At a median follow-up of 18.9 months, a significantly higher proportion of patients in the dabrafenib plus trametinib than chemotherapy group achieved the primary endpoint of an overall response (complete or partial) according to RANO criteria as assessed by independent review, at rates of 47% and 11%, respectively (risk ratio [RR]=4.31).
The clinical benefit rate, which additionally included stable disease for at least 24 weeks, was also significantly higher with dabrafenib plus trametinib than chemotherapy, at 86% versus 46% (RR=1.88).
And the median PFS was nearly threefold longer in the dabrafenib–trametinib arm than the chemotherapy arm, at 20.1 versus 7.4 months, which equated to a significant 69% reduction in the risk for disease progression or death with the targeted combination. The estimated 6-month PFS rates were 87% and 58%, respectively, while the 12-month rates were 67% and 26%.
Eric Bouffet, from the Hospital for Sick Children in Toronto, Ontario, Canada, and co-investigators report that adverse events (AEs) of grade 3 or worse occurred in a smaller proportion of patients receiving dabrafenib plus trametinib than chemotherapy, at 47% versus 94%.
The most common events of this severity in the dabrafenib–trametinib group were neutropenia (10%), pyrexia (8%), and weight gain (7%), while decreased neutrophil count (48%), neutropenia (30%), and anemia (24%) were most frequent in the chemotherapy group.
An identical 79% of participants in each group required dose adjustments or interruptions due to any-grade AEs, but fewer patients in the dabrafenib plus trametinib arm permanently discontinued due to AEs, at a rate of 4% compared with 18% in the chemotherapy arm.
Despite the more favorable safety profile, the researchers caution that “potential toxic effects with dabrafenib plus trametinib and the risk–benefit ratio should be evaluated on an individual basis, particularly because indefinite treatment may be required and the long-term safety of dabrafenib plus trametinib in this population is unknown.”
And they conclude: “Future studies are needed to evaluate functional outcomes (e.g., visual acuity), further molecular characterization, and most effective treatment duration.”
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